Breast cancer affects 1 in 8 women in the U.S. and is responsible for more than 40,000 deaths per year. Breast cancer risk is not homogeneously distributed among U.S. populations and factors responsible for differences in incidence are not yet understood. Breast cancer incidence in Latinas is 33% lower than in Non- Latina White women. We recently discovered a genetic variant that is only present in populations with Indigenous American ancestry (i.e., genetic ancestry from one of the original groups that populated the American continent before colonization), which provides protection from breast cancer risk. This polymorphism is located near the estrogen receptor 1 gene (ESR1) on chromosome 6, which has been repeatedly implicated in breast cancer. We have conducted preliminary experimental analyses that support the possibility that the genetic variant might be functional. We hypothesize that it influences ESR1 gene expression as well as expression of other genes that depend on the estrogen receptor for transcription. To test this hypothesis, we have established collaboration with the Instituto Nacional de Enfermedades Neoplsicas in Lima, Peru, where investigators have created a large repository of biospecimens, clinical data, tumor histology, treatment, and progression information. We will select biospecimens (formalin fixed paraffin embedded tumor blocks and blood samples) from 2,000 Peruvian women. There are no comparable resources available in the U.S. to study this polymorphism, which is much more common in Peru given the high average Indigenous American ancestry of this population (~80%). In Aim 1 we will examine the association between the Indigenous American genetic variant and tumor subtype, to confirm our original finding of a stronger association with tumors that are negative for the estrogen receptor, and further evaluate the subtype-specific effect, beyond just estrogen receptor characterization. In Aim 2 we will test the association between the variant and expression of the ESR1 gene, as well as expression of other genes that depend on estrogen for expression. In Aim 3, we will test the association between the genetic variant and expression of different versions of ESR1, since we hypothesize that the protective effect of the Indigenous American variant for ER negative disease could be acting through this mechanism. At the conclusion of these studies, we will have expanded our understanding of the mechanisms through which the Indigenous American variant reduces the risk of developing breast cancer and, in particular, the risk of the most aggressive and difficult to treat form of th disease. This project will provide the fundamental knowledge for the design of in-vitro and animal model experiments that could ultimately lead to the development of breast cancer preventive treatment for all women.